JP2009525962A - Azaindoles useful as Janus kinase inhibitors - Google Patents

Abstract

The present invention relates to compounds useful as protein kinases, particularly JAK family kinase inhibitors. The invention also provides pharmaceutically acceptable compositions comprising the compounds and methods of using the compositions in the treatment of various diseases, conditions or disorders. These compounds, and pharmacologically acceptable compositions thereof, include proliferative diseases, heart diseases, neurodegenerative diseases, autoimmune diseases, symptoms related to organ transplantation, inflammatory diseases, or immune-mediated diseases Useful in treating various diseases in patients or reducing their severity. The compounds and compositions provided by the present invention are also used in studies of JAK kinases in biological and pathological phenomena, studies of intracellular signaling pathways mediated by the kinases, and comparative evaluation against novel kinase inhibitors. Is also useful.

Description

  The present invention relates to the provision of compounds useful as inhibitors of Janus kinase (JAK). The invention also relates to pharmacologically acceptable compositions comprising the compounds of the invention and to the use of such compositions for the treatment of various diseases.

  Janus kinase (JAK) is a family of tyrosine kinases and is composed of JAK1, JAK2, JAK3 and TYK2. JAK plays an important role in the cytokine signaling system. Examples of downstream substances of JAK family kinases include transcriptional signal transducers and activators (STATs) of proteins and activator of transcription (STAT) proteins. JAK / STAT signaling includes allergy, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and blood malignant diseases such as leukemia and lymphoma Many have been reported to affect immune response abnormalities. JAK2 is also associated with polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic eosinophilic It has been reported that it can also be involved in myeloproliferative disorders including leukemia, eosinophilia syndrome and systemic mast cell disease.

  Thus, there is a great need for the development of compounds that are useful as inhibitors of protein kinases. In particular, development of compounds useful as inhibitors of JAK family kinases is desirable.

It has been found that the compounds according to the present invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of protein kinases (particularly JAK family kinases). These compounds have the general formula I
Or a pharmaceutically acceptable salt thereof, wherein X ¹ , R ¹ , R ² and R ³ are as defined herein.

  These compounds, and pharmacologically acceptable compositions thereof, include proliferative diseases, heart diseases, neurodegenerative diseases, autoimmune diseases, symptoms related to organ transplantation, inflammatory diseases, or immune-mediated diseases Useful in treating various diseases in patients or reducing their severity.

  The compounds and compositions provided by the present invention are also used in studies of JAK kinases in biological and pathological phenomena, studies of intracellular signaling pathways mediated by the kinases, and comparative evaluation against novel kinase inhibitors. Is also useful.

Definitions and General Terminology In this specification, the following definitions are used unless otherwise indicated. For the purposes of the present invention, the identification of chemical elements follows the CAS version of the Periodic Table of Elements and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, for general principles of organic chemistry, see “Organic Chemistry”, Thomas Sorell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry. 5”. , M.M. B. Smith and J.M. March, eds. John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

  As described herein, the compounds of the invention may be optionally substituted with one or more substituents as illustrated above or illustrated by the particular classification, subclass and chemical species of the invention. Good. The phrase “optionally substituted” is used interchangeably with the term “substituted or unsubstituted”. In general, the term “substituted” refers to the replacement of one or more hydrogen groups with a given substituent in a given structure, whether or not preceded by the term “optionally”. Unless otherwise specified, an optionally substituted group may have a substituent at each substitution position of the group. When two or more positions in a predetermined structure can be substituted with two or more substituents selected from a predetermined group, the substituents may be the same or different at each substituent position.

When the term “optionally substituted” as described herein precedes an enumeration, the term refers to the fact that all groups that follow in the enumeration can be substituted. If a free radical or structure as a substituent is not identified or defined as “optionally substituted”, the substituent or structure is not substituted. For example, when X is halogen, optionally substituted C _1-3 alkyl or phenyl, X is either an optionally substituted alkyl group or an optionally substituted phenyl group. May be. Similarly, when the term “optionally substituted” follows an enumeration, the term indicates that all groups in the above enumeration are substitutable unless otherwise indicated. For example, when X is halogen, C _1-3 alkyl or phenyl, and X may optionally be substituted with J ^X , both the C _1-3 alkyl group and the phenyl group are optionally substituted with J ^X May be. As will be apparent to those skilled in the art, groups such as hydrogen, halogen, NO ₂ , CN, NH ₂ , OH or OCF ₃ are not included because they are not substitutable groups.

  Combinations of substituents envisioned in this invention are preferably those that allow the formation of stable or chemically compatible compounds. As used herein, the term “stable” means that a compound is substantially unchanged when it is produced, detected, and preferably used for recovery, purification, and one or more purposes disclosed herein. Used when referring to compounds. In one embodiment, the stable compound or chemically usable compound is substantially free when held at a temperature of 40 ° C. or lower for at least one week in the absence of moisture or in other chemically reactive conditions. The compound does not change into

  As used herein, the term “aliphatic” or “aliphatic group” refers to a substituted or unsubstituted, such as a straight chain (ie, unbranched) or branched, that is fully saturated or that includes one or more unsaturated units. Means hydrocarbon chain. Unless otherwise specified, aliphatics contain 1-20 aliphatic carbon atoms. In one embodiment, the aliphatic contains 1-10 aliphatic carbon atoms. In other embodiments, aliphatic contains 1-8 aliphatic carbon atoms. In yet another embodiment, the aliphatic contains 1-6 aliphatic carbon atoms. In yet another embodiment, the aliphatic contains 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkylnyl groups. Other aliphatic examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl groups.

The term “alicyclic” group (or “carbocyclyl” or “cycloalkyl” group) refers to a hydrocarbon group that contains one or more units that are fully saturated or unsaturated, but that are not aromatic, It has a single binding site to the rest of the molecule, and every individual ring of the bicyclic ring system has 3-7 members. Unless otherwise specified, the term “alicyclic” group refers to a monocyclic C ₃ -C ₈ hydrocarbon group or a bicyclic C ₈ -C ₁₂ hydrocarbon group. Suitable alicyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Further examples of aliphatic include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cycloheptenyl groups.

  As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclic” includes fully saturated, or one or more unsaturated units, but is not aromatic and is present in the rest of the molecule. It refers to a monocyclic, bicyclic or tricyclic ring system having one binding site for it and one or more ring members being independently selected heteroatoms. In one embodiment, a “heterocycle”, “heterocyclyl”, or “heterocyclic” group is a 3-14 membered ring and one or more ring members are independently selected from oxygen, sulfur, nitrogen, or phosphorus. And each ring in such a system is composed of 3 to 7 ring members.

  Examples of heterocycles include the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1 -Imidazoli Nil, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl group; and the following bicyclic rings: 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, indolinyl, tetrahydro Examples include, but are not limited to, quinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydroimidazol-2-one groups.

The term “heteroatom” means one or more oxygen, sulfur, nitrogen, phosphorus, or silicon, including oxidized forms of nitrogen, sulfur, phosphorus or silicon, quaternized forms of basic nitrogen, or 3 Substitutable nitrogens present in the heterocycle are included, such as N in 1,4-dihydro-2H-pyrrolyl, NH in pyrrolidinyl or NR ⁺ in N-substituted pyrrolidinyl.

  As used herein, the term “unsaturated” means that a moiety has one or more units of unsaturation.

  The term “aryl” used to denote the structure of a portion or a relatively large portion in the term “aralkyl”, “aralkoxy” or “aryloxyalkyl” group refers to a monocyclic, bicyclic compound having a total of 6 to 14 members. Refers to cyclic and tricyclic carbocycles, where at least one ring in these systems is aromatic and each ring in the system is composed of 3 to 7 members, relative to the rest of the molecule Has a single binding site. The term “aryl” can be used interchangeably with the term “aryl ring”. Examples of aryl rings include phenyl, naphthyl, and anthracene.

  The term “heteroaryl” used to denote a partial or relatively large substructure in a “heteroaralkyl” or “heteroarylalkoxy” group refers to a total of 5 to 14 monocyclic, bicyclic, and tricyclic rings. Refers to a cyclic ring, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, each ring in the system is 3-7 membered; It has a single binding site for the rest of the molecule. The term “heteroaryl” can be used interchangeably with “heteroaryl ring” or “heteroaromatic”.

  Examples of heteroaryl rings include monocyclic: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg, 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg, 5-tetrazolyl), thiazolyl (eg, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg, 2-pyrazolyl), isothiazolyl, 1,2,3- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, Pyrazinyl, 1,3,5-triazinyl group and bicyclic: benzimidazolyl, benzofuryl, benzothiophenyl, indolyl (eg, 2-indolyl), purinyl, quinolinyl (eg, 2-quinolinyl, 3-quinolinyl, 4- Quinolinyl), and isoquinolinyl groups (eg, 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl groups), and the like, but are not limited thereto.

In one embodiment, an aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atoms of the aryl or heteroaryl group are selected from the groups listed in the definitions of R ² and R ⁴ below. Other suitable substituents include: halogen, —R 2 ^{O 3} , —OR 2 ^{O 3} , —SR 2 ^{O 3} , 1,2-methylenedioxy, 1,2-ethylenedioxy, R 2 ^O Phenyl (Ph) optionally substituted with R 2 ^O , O (Ph) optionally substituted with R 2 ^O , (CH ₂ ) _1-2 (Ph) optionally substituted with R 2 ^O optionally substituted _{^{CH = CH (Ph), -}} NO 2, -CN, -N (R O) 2, -NR O C (O) R O, -NR O C (S) R O, - _{^{NR O C (O) N (}} R O) 2, -NR O C (S) N (R O) 2, -NR O CO 2 R O, -NR O NR O C (O) R O, -NR O _{^{NR O C (O) N (}} R O) 2, -NR O NR O CO 2 R O, -C (O) C (O) R O, -C (O) CH 2 C _{^{O) R O, -CO 2 R}} O, -C (O) R O, -C (S) R O, -C (O) N (R O) 2, -C (S) N (R O) 2 , —OC (O) N (R ₂ ^O ₂ ) ₂ , —OC (OR ₂ ^{O 3} ), —C (O) N (OR 2 ^{O 3} ) R 2 ^{O 3} , —C (= NOR 2 ^O ) R 2 ^{O 3} , —S (O) ₂ R _{^{O, -S (O) 3 R}} O, -S (O) 2 N (R O) 2, -S (O) R O, -NR O S (O) 2 N (R O) 2, -NR O S (O) ₂ R ^O , —N (OR ^O ) R ^O , —C (═NH) —N (R ^O ) ₂ , or — (CH ₂ ) _0-2 NHC (O) R ^O
Wherein R 2 ^O is independently hydrogen, optionally substituted C _1-6 aliphatic, unsubstituted 5-6 membered heteroaryl or heterocycle, phenyl, —O (Ph) or —CH ₂ (Ph) or the two R 2 ^O in the same or different substituents are independently, together with the atoms to which each R 2 ^O group is attached, a 5-8 membered heterocyclyl, aryl, or heteroaryl ring or form, or 3-8 membered form a cycloalkyl ring, and having a such heteroaryl or heterocyclyl ring 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur .R ^O The optional substituents for aliphatic are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O (C _{1- 4 aliphatic),} NO _{2, CN, O 2 H, CO 2 (C} 1-4 aliphatic), O (halo _{C 1-4} aliphatic), or halo _{C 1-4} selected from aliphatic, and _{C 1-4} aliphatic in the above ^{R O} Are each unsubstituted).

In one embodiment, an aliphatic or heteroaliphatic, or non-aromatic heterocycle may contain one or more substituents. Suitable substituents at the saturated carbon of the aliphatic or heteroaliphatic or non-aromatic heterocycle are selected from the groups listed for the unsaturated carbon of the aryl or heteroaryl group, and further include:
= O, = S, = NHNR ^* , = NN (R ^* ) ₂ , = NNHC (O) R ^* , = NNHC (O) O (alkyl), = NNHS (O) ₂ (alkyl), or NR ^*
(However, each R ^* is independently selected from hydrogen or an optionally substituted C _1-6 aliphatic. The optional substituents in the aliphatic of R ^* are NH ₂ , NH (C _{1 -4} aliphatic), _{N (C 1-4 aliphatic) 2, halogen, C 1-4} aliphatic, OH, _{O (C 1-4 aliphatic), NO 2, CN, CO} 2 H, CO 2 ( C _1-4 aliphatic), O (halo C _1-4 aliphatic), or halo C _1-4 aliphatic, and each C _1-4 aliphatic in R ^* above is unsubstituted) .

In one embodiment, the optional substituents on the nitrogen of a non-aromatic heterocyclic _{^{ring, -R +, -N (R +}} ) 2, -C (O) R +, -CO 2 R +, -C (O _{^{) C (O) R +,}} -C (O) CH 2 C (O) R +, -S (O) 2 R +, -S (O) 2 N (R +) 2, -C (= S) _{^{N (R +) 2, -C}} (= NH) -N (R +) 2 , or _{^{-NR + S (O) 2 R}} + can be mentioned, ^{R +} is an optionally substituted hydrogen, optionally _{C 1- 6} aliphatic, optionally substituted phenyl, optionally substituted —O (Ph), optionally substituted —CH ₂ (Ph), optionally substituted — (CH _{2) 1-2} (Ph), or an optionally substituted -CH = CH (Ph), or oxygen, 1 to 4 heteroatoms independently selected from nitrogen or sulfur Or heteroaryl or heterocyclic 5-6 membered unsubstituted with child, or two R ^{+ (the} same substituent or different substituents) are independently together with the atoms to which each R ⁺ group is bound, Forms a 5-8 membered heterocyclyl, aryl or heteroaryl ring, or forms a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring is independently selected from nitrogen, oxygen or sulfur It has 1 to 3 heteroatoms. The optional substituents on the aliphatic or phenyl ring of R ⁺ are NH ₂ , NH (C _1-4 aliphatic), N (C _1-4 aliphatic) ₂ , halogen, C _1-4 aliphatic, OH, O _{(C 1-4 aliphatic), NO 2, CN, CO} 2 H, CO 2 (C 1-4 aliphatic), O (halo _{C 1-4} aliphatic), or halo _{(C 1-4} aliphatic And each C _1-4 aliphatic in R ⁺ is unsubstituted.

In one embodiment, as detailed above, when each R ^O (or R ⁺ or other variable structure as defined herein) occurs independently, each variable structure is bound. Together with the atoms to form a 5-8 membered heterocyclyl, aryl or heteroaryl ring, or a 3-8 membered cycloalkyl ring. Rings formed by two independent R ^O (or R ⁺ or other variable structures as defined herein) together with the atoms to which each variable structure is attached include the following: Not limited to:
a) a ring in which two independent R ^O (or R ⁺ or other variable structure as defined herein) are bonded to and formed with the same atom, eg, N (R ^O ) ₂ : (Wherein both R 2 ^O together with the nitrogen atom form a piperidin-1-yl, piperazin-1-yl or morpholin-4-yl group);
b) a ring in which two independent R ^O (or R ⁺ or other variable structure as defined herein) are bonded to different atoms and formed with both of those atoms, eg, two OR ^O When the phenyl group is substituted as follows:

These two R 2 ^O's are condensed with the oxygen atom to which they are attached, and a six-membered ring containing oxygen

Form. In the present invention, R ^O (or R ⁺ or other variable structure similarly defined in the present specification) independently exists in two forms, each variable structure has various other types together with the atoms to which they are bonded. It will be appreciated that the embodiments that form the ring are not limited to the specific exemplary embodiments described above.

In one embodiment, the alkyl chain or aliphatic chain may optionally contain other atoms or groups. This means that the methylene unit of the alkyl or aliphatic chain may be optionally substituted with other atoms or groups. Examples of such atoms or groups include, but are not limited to:
_{-NR -, - O -, -} S -, - CO 2 -, - O (C) O -, - C (O) C (O) -, - C (O) -, - C (O) NR- , -C (= N-CN) -, - NRC (O) -, - NRC (O) O -, - S (O) 2 NR -, - NRS (O) 2 -, - NRC (O) NR- , —OC (O) NR—, —NRS (O) ₂ NR—, —S (O) — or —S (O) ₂ — (wherein R is defined herein). Unless otherwise stated, chemically substituted compounds are formed by optional substitution. Such optional intervening may be present both in the middle of the chain and at both ends of the chain, i.e. both at the binding site and / or at the end. As long as a chemically stable compound is obtained, the two intervening portions may be adjacent to each other in the chain. Unless otherwise specified, when the substitution or interposition is present at the terminal end, the substituted atom is bonded to the terminal H. For example, when —CH ₂ CH ₂ CH ₃ is optionally blocked with —O—, the resulting compound can be —OCH ₂ CH ₃ , —CH ₂ OCH ₃ or —CH ₂ CH ₂ OH.

In this specification, when a notation in which a bond with a substituent extends from the center of one ring in a polycyclic system (shown below), the substituent is present in any ring in the polycyclic system. It means that it may be combined with a substitution position. For example, FIG. A means that it may be substituted at any position shown in FIG.

This also applies to polycyclic systems in which any ring system (sometimes indicated by a dotted line) is fused. For example, in FIG. C, X becomes a substituent that may optionally be attached to both ring A and ring B.

However, when two rings in a polycyclic system each have a different substituent drawn from the center of each ring, unless otherwise specified, each substituent is a substituent for the ring to which it is attached. To do. For example, in FIG. D, Y is an optional substituent for ring A only and X is an optional substituent for ring B only.

  Unless otherwise stated, structures shown herein include all isomeric forms (eg, enantiomers, diastereomers, and geometric (or structural) isomers) of that structure, eg, each asymmetric It is meant to include R and S configurations relative to the center, (Z) and (E) double bond isomers, and (Z) and (E) structural isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or structural) isomer mixtures for the compounds of the present invention are within the scope of the invention.

Unless otherwise stated, all tautomeric forms for the compounds of the invention are within the scope of the invention. Further, unless otherwise indicated, the structures shown herein are meant to include compounds that differ only in the presence of one or more isotopically labeled atoms. For example, compounds of the invention having the same structure except that hydrogen is substituted with deuterium or tritium, or carbon is substituted with ¹³ C or ¹⁴ C labeled carbon are within the scope of the invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

Description of the compounds according to the invention:
The present invention relates to a compound of formula I,
Or a pharmaceutically acceptable salt thereof. Wherein R ³ is hydrogen, Cl or F, X ¹ is N or CR ⁴ and R ² is hydrogen, F, R ′, OH, OR ′, COR ′, COOH, COOR ′, CONH ₂ , CONHR ', CON _{(R') 2} or CN, ^{R 4} is hydrogen, F, R ', OH, oR', COR ', COOH, COOR', CONH 2, CONHR ', CON (R') 2 or CN Or R ² and R ⁴ together form a 5-7 membered aryl or heteroaryl ring optionally substituted with 1 to 4 R ¹⁰ , and R ′ is 1 to 4 of a good _{C 1-3} aliphatic optionally substituted with ^{R 5,} each ^{R 5} is _{halogen, CF 3, OCH 3, OH} , SH, NO 2, NH 2, SCH 3, NCH 3, CN or or are independently selected from unsubstituted C _1-2 aliphatic, or two R ⁵ groups to bond them Together with the carbon atom form a cyclopropyl ring or C = O, each ^{R 10} is _{halogen, OCH 3, OH, NO 2} , NH 2, SH, from SCH 3, _NCH 3, CN or unsubstituted _{C 1-2} aliphatic Independently selected, R ¹ is

And R ″ is hydrogen or C _1-2 aliphatic optionally substituted with 1 to 3 groups of —R ¹¹ , wherein each R ¹¹ is halogen, OCH ₃ , OH, SH , NO ₂ , NH ₂ , SCH ₃ , NCH ₃ , CN, CON (R ¹⁵ ) ₂ or unsubstituted C _1-2 aliphatic or two R ¹¹ groups to which they are attached Forms a cyclopropyl ring or C═O with carbon atoms, R ⁶ is a C _1-4 aliphatic compound optionally substituted with 1 to 5 R ¹² groups, each R ¹² is halogen, OCH ₃ , OH, NO ₂ , NH ₂ , SH, SCH ₃ , NCH ₃ , CN or unsubstituted C _1-2 aliphatic or two R ¹² groups are the carbon atoms to which they are attached Together with a cyclopropyl ring, ring A is from N, O or S 4 to 8 membered saturated nitrogen-containing rings containing up to 2 heteroatoms selected and optionally substituted with 1 to 4 R ¹³ groups, each R ¹³ being halogen, R ′, NH ₂ , NHR ′, N (R ′) ₂ , SH, SR ′, OH, OR ′, NO ₂ , CN, CF ₃ , COOR ′, COOH, COR ′, OC (O) H, OC (O) R ′ , CONH ₂ , CONHR ′, CON (R ′) ₂ , NHC (O) R ′ or NR′C (O) R ′, or any two R ¹³ groups are the same substituent or 3-7 membered saturated, unsaturated, or partially optionally substituted with 1 to 3 R ⁵ groups with different substituents and one or more atoms to which each R ¹³ group is attached a carbocyclic or heterocyclic saturated to form, ^{R 8} is 1-5 optionally substituted with ^{R 12} groups _{C 1-4} cycloaliphatic A family compound, or ^{R 9} is _{C 1-2} alkyl, or, ^{R 8} and ^{R 9} together, the 1-5 ^{R 12} optionally may be substituted 3-7 membered group carbocycle R ¹⁴ is hydrogen or an unsubstituted C _1-2 alkyl group, R ¹⁵ is hydrogen or an unsubstituted C _1-2 alkyl group, and R ⁷ is up to 6 It is a _C2-3 aliphatic or alicyclic group optionally substituted with F.

In one embodiment, the compounds of the invention are represented by one of formulas IA or IB.

In one embodiment, R ³ is hydrogen or Cl. In a further embodiment, R ³ is Cl. In a further embodiment, R ³ is hydrogen.

In one embodiment, R ² is hydrogen, F, R ′, OH or OR ′. In a further embodiment, R ² is hydrogen or F.

In one embodiment, the compound is represented by Formula IA and R ⁴ is hydrogen, F, R ′, OH, or OR ′. In other embodiments, R ⁴ is hydrogen or F. In a further embodiment, R ⁴ is F and R ² is hydrogen. In other embodiments, R ² is F and R ⁴ is hydrogen. In other embodiments, both R ² and R ⁴ are hydrogen. In a further embodiment, R ³ is Cl. In an alternative embodiment, R ³ is hydrogen.

In other embodiments, the compound is Formula IA, and R ² and R ⁴ together form a 6-membered aryl ring. In a further embodiment, R ³ is Cl. In another embodiment, R ³ is hydrogen.

In other embodiments, R ⁷ is CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ CHF ₂ , CH ₂ CH ₂ F, CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CF ₃ , CH ₂ CH ₂ CH _2. F or CH ₂ CH ₂ CHF ₂ . In further embodiments, R ⁷ is CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ CH ₃ or CH ₂ CH ₂ CF ₃ . In yet another embodiment, R ⁷ is CH ₂ CF ₃ .

In other embodiments, R ″ is hydrogen or CH _{3. In} further embodiments, R ″ is hydrogen.

In other embodiments, R ¹⁴ is hydrogen. In yet another embodiment, R ¹⁵ when present is hydrogen. In other embodiments, R ¹⁵ is absent.

In another embodiment, this invention relates to the provision of a compound of formula II.
Wherein X ^1A is N, CH or CF, and R ^1A is

It is. In further embodiments, R ⁷ is CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ CH ₃ or CH ₂ CH ₂ CF ₃ . In yet another embodiment, R ⁷ is CH ₂ CF ₃ .

In another embodiment, this invention relates to the provision of a compound of formula III.
Wherein X ^1A is N, CH or CF, and R ^1A is


It is. In further embodiments, R ⁷ is CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ CH ₃ or CH ₂ CH ₂ CF ₃ . In yet another embodiment, R ⁷ is CH ₂ CF ₃ .

In other embodiments of any of formulas I, II, or III, R ⁶ is

Selected from.

In a further embodiment, R ⁶ is

Selected from.

In yet another embodiment, R ⁶ is

Selected from.

In other embodiments of any of formulas I, II, or III, ring A is

And R ¹³ ′ is hydrogen or R ¹³ .

In a further embodiment, ring A is

It is.

In a further embodiment, ring A is

It is.

In one embodiment, each R ¹³ is halogen, R ′, NH ₂ , NHR ′, N (R ′) ₂ , SH, SR ′, OH, OR ′, NO ₂ , CN, CF ₃ , COOR ′, COOH, Independently selected from COR ′, OC (O) R ′ or NHC (O) R ′, or any two groups of R ¹³ may be bonded to the same or different substituents with each R ¹³ group attached 1 Together with one or more atoms form a 3-7 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring which may be optionally substituted with 1 to 3 R ⁵ groups.

In one embodiment of the invention, R ¹³ is absent. In other embodiments, Ring A is substituted with 1 R ¹³ . In a further embodiment, said one R ¹³ is OH, CH ₃ , F, OR ′ or NHR ′. In yet another embodiment, R ′ is a C _1-2 alkyl or C _2-3 alkenyl group. In other embodiments, R ¹³ is OH.

In other embodiments of any of formulas I, II, or III, R ⁸ and R ⁹ are both

In which one or more carbon atoms in the ring are independently optionally substituted with N, O or S.

In other embodiments of any of formulas I, II, or III, R ⁸ and R ⁹ are

It is.

In a further embodiment, R ⁸ and R ⁹ are

It is.

In yet another embodiment, R ⁸ and R ⁹ are

It is.

In yet another embodiment, R ⁸ and R ⁹ are

It is.

In another embodiment, the present invention relates to the provision of compounds of formula I, IA, IB, II or III. The compound is more effective than the compound inhibits one or more kinases selected from Aurora-1 (AUR-B), Aurora-2 (AUR-A), Src, CDK2, Flt-3 or c-Kit. a low _{K i} (i.e. more strongly), inhibiting JAK kinase. In another embodiment, the present invention relates to the provision of compounds of formula I, IA, IB, II or III. The compound, wherein said compound inhibits JAK2, Aurora-1, Aurora- 2, Src, CDK2, Flt-3 or JAK3 with a lower _{K i} than inhibits one or more kinases selected from c-Kit .

In another embodiment, the present invention relates to the provision of a compound of any of formulas I, IA, IB, II or III. The compound inhibits JAK3 with a K _i of less than 0.1 μM. In a further embodiment, the invention relates to the provision of a compound of any of formulas I, IA, IB, II or III. The compound inhibits JAK3 with a K _i of less than 0.01 μM. In another embodiment, the present invention relates to the provision of a compound of any of formulas I, IA, IB, II or III. The compounds inhibit the JAK3 with _{K i} of less than 0.01 [mu] M, inhibit Aurora-2 at least 5 times higher _{K i} than _{K i} in the case of JAK3. In a further embodiment, the invention relates to the provision of a compound of any of formulas I, IA, IB, II or III. The compounds inhibit the JAK3 with _{K i} of less than 0.01 [mu] M, inhibit Aurora-2 at least 10-fold higher _{K i} than _{K i} in the case of JAK3.

In another embodiment, the present invention relates to the provision of compounds of formula I, IA, IB, II or III. The compound inhibits JAK3 in a cellular assay with an IC ₅₀ of less than 5 μM. In a further embodiment, the compound inhibits JAK3 in a cellular assay with an IC ₅₀ of less than 1 μM.

In another embodiment, the compound is in a cellular assay, wherein the compound is selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3 or in c-Kit in a cellular assay. Inhibits JAK3 with an IC ₅₀ of at least 5 times less than inhibiting the kinase. In another embodiment, the present invention relates to the provision of compounds of formula I, IA, IB, II or III. In said compound cellular assay, inhibits JAK3 with _{an IC 50} of less than 5 [mu] M, _{IC 50} of JAK2 is at least five times higher than the _{IC 50} of JAK3. In a further embodiment, the compound in a cellular assay, inhibits JAK3 with _{an IC 50} of less than 1 [mu] M, _{IC 50} of JAK2 is at least five times higher than the _{IC 50} of JAK3. In a further embodiment, the compound in a cellular assay, inhibits JAK3 with _{an IC 50} of less than 5 [mu] M, _{IC 50} of JAK2 is at least 10-fold higher than the _{IC 50} of JAK3. In a further embodiment, the compound in a cellular assay, inhibits JAK3 with _{an IC 50} of less than 1 [mu] M, _{IC 50} of JAK2 is at least 10-fold higher than the _{IC 50} of JAK3. In yet another embodiment, the invention relates to the provision of a compound of formula I, IA, IB, II or III. In said compound cellular assay, inhibits JAK3 with _{an IC 50} of less than 1 [mu] M, _{IC 50} of JAK2 is at least 5 times higher than _{IC 50} of JAK3, wherein said compound inhibits JAK3 with _{K i} of less than 0.01 [mu] M, inhibiting Aurora-2 at least 5 times higher _{K i} than JAK3 the _{K i.} In yet another embodiment, the compound is in a cellular assay, inhibits JAK3 with _{an IC 50} of less than 1 [mu] M, _{IC 50} of JAK2 is at least 10 times higher than the _{IC 50} of JAK3, the compound of less than 0.01 [mu] M _{K i} Inhibits JAK3 and inhibits Aurora-2 with a K _i that is at least 10 times higher than the K _{i of} JAK3.

In other embodiments, the invention relates to the provision of the compounds of Table 1, Table 2, or Table 3.
Table 1











Table 2











Table 3

Use, formulation and administration: pharmaceutically acceptable compositions:
In another embodiment, the present invention relates to the provision of a pharmaceutical composition comprising a compound of formula I, IA, IB, II or III.

  In other embodiments, the composition further comprises a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulator or immunosuppressant, a neurotrophic factor, a drug for treating heart disease, a destructive bone disease. Selected from drugs for treating, drugs for treating liver disease, antiviral drugs, drugs for treating blood disorders, drugs for treating diabetes, or drugs for treating immunodeficiency diseases Contains therapeutic drugs.

  In another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the compound in the composition of the present invention is an amount effective to moderately inhibit protein kinases, particularly JAK family kinases, in a biological sample or patient. The compositions of the present invention are preferably formulated immediately prior to administration to a patient in need of such compositions. Most preferably, the compositions of the present invention are formulated for oral administration to a patient.

  As used herein, the term “patient” means an animal, preferably a mammal, most preferably a human.

  Accordingly, in other embodiments of the invention, pharmacologically acceptable compositions are provided, such compositions comprising a compound described herein, and optionally a pharmaceutically acceptable carrier, Contains adjuvants or excipients. In certain embodiments, such compositions optionally include one or more additional therapeutic agents.

  It will be appreciated that the compounds of the present invention may be in free form when used in therapy, or optionally as pharmacologically acceptable derivatives thereof. The pharmacologically acceptable derivatives in the present invention include pharmacologically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative, which is administered to a patient in need thereof. Include, but are not limited to, those that are capable of providing the compounds specifically described herein, or their metabolites or residues thereof, directly or indirectly. As used herein, the term “metabolite having inhibitory activity or residue thereof” means that the metabolite or residue thereof is also an inhibitor of JAK family kinases.

  As used herein, the term “pharmacologically acceptable salt” refers to undesired toxicity, irritation, and allergy in contact with human and lower animal tissues within the scope of valid medical judgment. It refers to a salt that can be used without causing a reaction and the like, and the ratio of profit to disadvantage is appropriately balanced.

Pharmacologically acceptable salts are well known in the art. For example, S.M. M.M. Berge et al. The pharmacologically acceptable salts described in detail in Pharmaceutical Sciences, 66, 1-19, 1977 are hereby incorporated by reference. Pharmacologically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmacologically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or acetic acid, oxalic acid, maleic acid, tartaric acid, for example. And amino acids obtained by organic acids such as succinic acid or malonic acid, or other methods used in the field of ion exchange and the like. Other pharmacologically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulphate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl Sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulphate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate , Malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate Oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Is mentioned. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C _1-4 alkyl) ₄ salts. The present invention further encompasses quaternized forms of the basic nitrogen-containing groups of the compounds disclosed herein. By the quaternization, a water-soluble or oil-soluble or dispersible product may be obtained. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Other pharmacologically acceptable salts include amine cations, such as halides, hydroxides, carboxylates, sulfates, phosphates, optionally formed using non-toxic ammonium, quaternary ammonium, and counterions. Examples include nitrates, lower alkyl sulfonates, and aryl sulfonates.

  As mentioned above, the pharmacologically acceptable compositions of the present invention further comprise a pharmacologically acceptable carrier, adjuvant or excipient, and in particular for use in the present invention, the specific dosages described above. Any solvent, diluent, or other liquid excipient, dispersion or suspension aid, surfactant, isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant, as appropriate for the form Etc. Remington's Pharmaceutical Sciences, 16th edition, E.I. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used for the formulation of pharmacologically acceptable compositions, and known pharmaceutical techniques using them. The disclosure of which is incorporated herein by reference. Conventionally known carrier media produce compounds of the present invention, such as causing undesirable biological effects, or otherwise causing undesirable interactions with other components in a pharmacologically acceptable composition. Use thereof is understood to be within the scope of the present invention, unless otherwise compatible.

Materials that can function as pharmacologically acceptable carriers include, but are not limited to, the following:
Ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum proteins, buffer substances such as phosphate, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes For example, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, wool Fats, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Malt; gelatin; talc; pharmaceutical additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; For example, propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid, pyrogen-free water; isotonic saline; Ringer's solution; And phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. In addition, a coloring agent, a release agent, a coating agent, a sweetener, a flavoring agent and a flavoring agent, an antiseptic and an antioxidant may be optionally contained in the composition.

  As used herein, the term “significantly inhibits” refers to kinase activity between a sample comprising a compound of the invention and JAK kinase and a similar sample comprising JAK kinase in the absence of the compound, In particular, it means that JAK family kinase activity is significantly different.

  The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implant container. The term “parenteral” as used herein includes administration by subcutaneous, intravenous, intramuscular, intraarticular, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Suitably the composition is administered orally, intraperitoneally or intravenously. When the composition of the invention is injected aseptically, it is administered as an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension (eg, a 1,3-butanediol solution) in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium.

  For this purpose a blend of fixed oils comprising synthetic mono- or diglycerides may optionally be used. Fatty acids (eg oleic acid and its glyceride derivatives) are useful in injectable formulations because they are natural pharmacologically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions are diluents or dispersants for long chain alcohols such as carboxymethylcellulose, or similar dispersants commonly used in formulating pharmacologically acceptable dosage forms such as emulsions and suspensions. An agent may be contained. Other commonly used surfactants (eg Tween, Span) and pharmacologically acceptable solids and liquids, or other emulsifiers or biological applications commonly used in the manufacture of other dosage forms You may formulate using the enhancer of ability.

  The pharmacologically acceptable composition of the present invention may be orally administered in an orally acceptable dosage form such as, but not limited to, a capsule, a tablet, an aqueous suspension or an aqueous solution. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate may be added as usual. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are used for oral administration, the active ingredient is mixed with emulsifying and suspending agents. If necessary, an appropriate amount of a sweetening agent, a flavoring agent and a flavoring agent may be added.

  Alternatively, the pharmacologically acceptable composition of the invention may be administered rectally in the form of a suppository. Such suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but becomes liquid at rectal temperature and melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

  The pharmacologically acceptable compositions of the present invention may be administered topically, particularly when the treatment goal is a disease of a region or organ that is readily accessible by topical administration (eg, eye, skin, or lower intestinal tract). preferable. Suitable topical formulations are prepared for direct administration to such areas or organs.

  Topical administration to the lower intestinal tract can be accomplished with a rectal suppository formulation (see above) or a suitable enema formulation. Alternatively, a topical transdermal patch may be used.

  For topical administration, the pharmacologically acceptable composition may be formulated as a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers used for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmacologically acceptable composition may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmacologically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

  When used for ophthalmic administration, the pharmacologically acceptable composition is, for example, as a fine suspension in isotonic pH-adjusted sterile saline or other aqueous solution, or preferably isotonic. PH adjusted sterile saline solution or other aqueous solution may be prepared, and a preservative such as benzylalkonium chloride may or may not be used. Alternatively, when used for ophthalmic administration, a pharmacologically acceptable composition may be added to an ointment such as petrolatum. The pharmacologically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared by techniques well known in the art of pharmaceutical formulation and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other common May be prepared as a saline solution using any suitable solubilizer or dispersant.

  Most preferably, the pharmacologically acceptable compositions of the present invention are formulated for oral administration.

  Liquid dosage forms for oral administration include, but are not limited to, pharmacologically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active compounds, inert diluents commonly used in the art (eg water or other solvents), solubilizers and emulsifiers (eg ethyl alcohol, isopropyl alcohol, ethyl carbonate, Ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide), oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofur It may contain furyl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof. Oral compositions may contain adjuvants (eg, wetting agents, emulsifying agents and suspending agents), sweetening agents, flavoring agents and flavoring agents in addition to the inert diluent.

  Injectable preparations (eg, sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion (eg, a solution in 1,3-butenediol) in a diluent or solvent acceptable for nontoxic parenteral use. ). Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.A. S. P and isotonic sodium chloride solutions. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium. For this purpose, fixed oil blends comprising synthetic mono- or di-glycerides may be used. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

  Injectable preparations may be sterilized, for example, by filtration through a bacteria-retaining filter, or sterile agents that can be dissolved or suspended in sterile water or other sterile injectable medium prior to use can be prepared as a sterile solid composition. It may be added in the form and sterilized.

  In order to prolong the effect of the compounds of the present invention, it may be desirable to delay the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using crystalline or amorphous materials with low water solubility. In this case, the absorption rate of the compound depends on the dissolution rate as well as the crystal size and crystal morphology. Alternatively, absorption of a parenterally administered compound form can be delayed by dissolving or suspending the compound in an oil vehicle. Injectable sustained release forms can be prepared by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. It is also possible to arbitrarily select a polymer having a ratio of polymer to compound and a specific property to be used to control the release rate of the compound. Other examples of biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable sustained-release preparations can also be prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

  Compositions for rectal or vaginal administration are preferably in the form of suppositories. The compounds of the present invention are suitable non-irritating pharmaceutical additives or carriers such as cocoa butter, polyethylene glycol, or active at ambient temperature but liquid at body temperature and melted in rectum or vaginal cavity They can be prepared by mixing with a suppository wax that releases the compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is at least one inert, pharmacologically acceptable pharmaceutical additive or carrier, such as sodium citrate or dicalcium phosphate and / or a) a filler or excipient. Agents (eg starch, lactose, sucrose, glucose, mannitol and silicic acid),
b) binders (eg carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic),
c) a wetting agent (eg glycerol),
d) disintegrants (eg agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate),
e) a solution retention agent (eg paraffin),
f) an absorption promoter (eg, a quaternary ammonium compound),
g) wetting agents (eg cetyl alcohol and glycerol monostearate),
h) Mix with absorbents (eg kaolin and valve and knight year), and i) lubricants (eg talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, a buffer may be included in the preparation.

  Also, solid compositions of the same type as excipients such as lactose or lactose and high molecular weight polyethylene glycols may be used as fillers in soft and hard filled gelatin capsules. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. These may optionally contain opacifiers and may be compositions that release the active ingredient alone or preferentially in a predetermined portion of the intestinal tract, optionally in delayed form. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of the same type as excipients such as lactose or lactose and high molecular weight polyethylene glycols may also be used as fillers in soft and hard filled gelatin capsules.

  The active compound may also be enclosed in microcapsules having one or more pharmaceutical additives as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain additional materials other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is usual. . In the case of capsules, tablets and pills, a buffer may be included in the preparation. These may optionally contain opacifiers and may be compositions that release the active ingredient alone or preferentially in a predetermined portion of the intestine, optionally in delayed form. Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalations and patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ointments (ie ear drops and eye drops) are also considered within the scope of the present invention. The present invention further includes the use of transdermal patches, which are further advantageous in controlling the transport of compounds to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers may be used to facilitate the transport of the compound to the skin. A rate controlling membrane may be provided, or the compound may be dispersed in a polymer matrix or gel to control the absorption rate.

  For ease of administration and uniformity of dosage, the compounds of the present invention are preferably formulated in unit dosage form. As used herein, the term “unit dosage form” refers to a physically separated unit of drug appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of valid medical judgment. Particularly effective dosage levels for a particular patient or organism can vary depending on various factors such as the disease to be treated and the severity of the disease; the activity of the particular compound used; the particular composition used; age; Well known in the medical field; gender and patient's daily food; administration time, route of administration, and excretion rate of the specific compound used; treatment time; drugs used in combination with or simultaneously with the specific compound used) May depend on other factors.

  When preparing a composition in a single dosage form, the amount of the compound of the invention mixed with the carrier material will vary depending on the recipient being treated, the particular type of administration, but preferably The composition is prepared such that an inhibitor of 0.01-100 mg / kg body weight / day can be administered to a patient receiving the composition.

  Depending on the particular condition or disease to be treated or prevented, other therapeutic agents normally administered for the treatment or prevention of this condition may be included in the compositions of the present invention. As used herein, additional therapeutic agents normally administered for the treatment or prevention of such specific diseases or conditions are those known as “agents appropriate to the disease or condition to be treated” Also good.

  For example, chemotherapeutic drugs or other antiproliferative agents may be combined with the compounds of the present invention to treat proliferative diseases and cancer. For example, known chemotherapeutic agents include, but are not limited to, Gleevec® (imatinib mesylate), adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon and platinum derivatives.

Other examples of agents that may be combined with the inhibitors of the present invention include, but are not limited to: Alzheimer's disease therapeutics (eg Alicept® and Excelon®); Drugs for Parkinson's disease (eg L-DOPA / carbidopa, entacapone, lopinlol, paramipexol, bromocriptine, pergolide, trihexefendil, and amantadine); drugs for multiple sclerosis (MS) (eg β-interferon (eg, Avonex® and Rebif®), Copaxone®, and Mitoxantrone); asthma treatments (eg, albuterol and Singulair®); schizophrenia treatments (eg, diplexa) , Resperdal, Roquel and haloperidol); anti-inflammatory drugs (eg corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine); immunomodulators and immunosuppressants (eg cyclosporine, tacrolimus, rapamycin, mycophenolate) Mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine);
Neurotrophic factors (eg acetylchlorinsterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole), as well as antiparkinson drugs, heart disease treatments (eg β-blockers, ACE inhibitors, diuretics) Nitrates, calcium channel blockers, and statins); liver disease drugs (eg, corticosteroids, cholestyramine, interferons, and antiviral drugs); As well as therapeutic agents for immunodeficiency diseases (eg gamma globulin).

  The amount of additional therapeutic agent included in the compositions of the present invention does not exceed that normally contained in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein ranges from about 50% to 100% of the amount normally used in a composition comprising that therapeutic agent as the only active agent.

Use of the Compounds and Compositions of the Invention In another embodiment, the invention relates to the provision of a method for inhibiting JAK kinase activity in a patient comprising administering to the patient the compounds and compositions of the invention.

  In another embodiment, the invention relates to providing a method of treating or reducing the severity of a JAK-mediated condition or disease in a patient. As used herein, the term “disease mediated by JAK” refers to various diseases or other deleterious symptoms known to involve JAK family kinases (particularly JAK2 or JAK3). In a further embodiment, the present invention includes a method of treating a disease mediated by JAK3. Such symptoms include solid and hematological malignancies such as leukemia and lymphoma, as well as allergic or type I hypersensitivity reactions, asthma, transplant rejection and other autoimmune diseases, graft-versus-host diseases, rheumatoid arthritis, muscle Examples include, but are not limited to, immune responses such as neurodegenerative disorders such as amyotrophic lateral sclerosis and multiple sclerosis, and familial amyotrophic lateral sclerosis (FALS).

  In another embodiment, the invention includes administering to the patient a compound or composition of the invention, a proliferative disorder, heart disorder, neurodegenerative disorder, autoimmune disease, organ transplant disorder, inflammatory It relates to the provision of a method for treating or reducing the severity of a disease symptom selected from a disorder, an immunodeficiency or an immunologically mediated disorder.

  In a further embodiment, the method comprises a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, a diabetes therapeutic agent, or Further comprising administering to the patient an additional therapeutic agent selected from immunodeficiency therapeutic agents, wherein the additional therapeutic agent is appropriate for the disease being treated, wherein the additional therapeutic agent is a unit It may be administered as a dosage form, or may be administered separately from or simultaneously with the composition as part of a multi-dose form.

  In one embodiment, the disease or disorder is an allergic or type I hypersensitivity reaction, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig) Disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion / ischemia, cerebral infarction, baldness, transplant rejection, graft-versus-host disease, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple Sclerosis, and solid and hematological malignancies such as leukemia and lymphoma. In a further embodiment, the disease or disorder is asthma. In another embodiment, the disease or disorder is transplant rejection. In another embodiment, the disease or disorder is rheumatoid arthritis.

  In another embodiment, the compounds or compositions of the invention may be used for the treatment of myeloproliferative disorders. In one embodiment, the myeloproliferative disorder is polycythemia vera, basic thrombocythemia, or chronic idiopathic myelofibrosis. In another embodiment, the myeloproliferative disorder is dysplasia with myelofibrosis, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hyperacidic syndrome, systemic obesity Cellular disease, atypical CML or juvenile myelomonocytic leukemia.

  In another embodiment, the invention relates to the use of a compound of formula I, IA, IB, II or III for the treatment of a disease mediated by JAK. In a further embodiment, the invention relates to the use of said compound for the treatment of any of the above diseases. In another embodiment, the invention relates to the use of a compound of formula I, IA, IB, II or III for the manufacture of a medicament for the treatment of a disease mediated by JAK. In a further embodiment, the present invention relates to the use of said compound for the manufacture of a medicament for the treatment of any of the above diseases.

  In another embodiment, the invention relates to providing a method of inhibiting JAK kinase activity in a biological sample, the method comprising contacting said biological sample with a compound or composition of the invention.

  As used herein, the term “biological sample” means an ex vivo sample, cultured cells or extracts thereof, tissue or organ samples or extracts thereof, biopsies obtained from mammals or extracts thereof, Examples include, but are not limited to, blood, saliva, urine, excrement, semen, tears or other body fluids or extracts thereof.

  Inhibition of kinase activity (particularly JAK kinase activity) in a biological sample is useful for a variety of purposes well known in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and bioassay.

  In certain embodiments of the invention, an “effective amount” or pharmacologically acceptable amount of the compound is an amount effective to treat or reduce the severity of one or more of the aforementioned disorders. The compounds and compositions according to the methods of the invention can be administered using any amount and any route of administration to treat or reduce the severity of the disorder or disease. The specific required amount depends on the race, age and patient health, the severity of infection, the drug used, the mode of administration, etc., and varies from patient to patient.

  In another embodiment, the methods of the invention include the additional step of separately administering additional therapeutic agents to the patient. If these additional therapeutic agents are administered separately, they can be administered to the patient prior to, during or after administration of the composition of the present invention.

  The compound of the present invention or a pharmacological composition thereof may be applied to an implantable medical device such as an artificial joint, an artificial valve, a blood vessel substitute, a stent, or a catheter. For example, vascular stents have been used to overcome restenosis (the narrowing of blood vessel walls after injury), but patients with stents or other implantable medical devices are at risk of clot formation or platelet activation. Sex existed. Thus, this undesirable situation can be prevented or reduced by pre-coating the device with a pharmacologically acceptable composition comprising a compound of the present invention.

  General methods for preparing suitable coatings and coated implantable devices are described in US Pat. Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally further be coated with a suitable topcoat of fluorosilicone resin, polysaccharide, polyethylene glycol, phospholipid or combinations thereof. Implantable devices coated with the compounds of the present invention are another embodiment of the present invention. The compound may be coated onto an implantable device, such as a bead, and prepared as a “drug stock” with a polymer or other molecule, thereby releasing the drug over a longer period of time than administering an aqueous solution of the drug. It becomes possible.

Methods of Compound Synthesis and Identification The compounds of the present invention can usually be prepared by well-known methods for analogous compounds or by the methods represented in the examples below. For example, see the description of WO 2005/095400 pamphlet (the entire disclosure is incorporated in the present invention).

  In one embodiment, all cited references are incorporated herein by reference. All abbreviations, symbols and conventions in the present invention are synonymous with those used in known scientific literature. For example, Janet S. Edited by Dodd, ACS Style Guide: A Manual for Authors and Editors, 2nd Ed. , Washington, D .; C. : American Chemical Society, 1997 (incorporated herein by reference).

Example 1: Preparation of compounds of the present invention
General synthesis method

Process 1
Boc-valine (1; R ₁ = Me, 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 mL, 0.02 mol). To a stirred solution of 06 mol) was added a solution of trifluoroethylamine HCl (2.92 g, 0.022 mol) in 100 mL DCM. The reaction mixture was stirred for 16 hours. Concentrated to dryness, redissolved in EtOAc and washed sequentially with 0.5 N HCl, NaHCO ₃ and saturated aqueous salt. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give compound 2, 5.4 g (98%) as a white solid.

Process 2
Compound 2 (5.32 g, 0.0197 mol) was deprotected with a 1: 1 mixture of DCM / TFA for 45 minutes at room temperature. Drying and concentration gave the intermediate amine that was used directly in the next step. 5-Fluoro-2,4-dichloropyrimidine (3; R = F; 3.28 g, 0.0197 mol), crude amine TFA salt (5.25 g, 0.0197 mol) and DIEA (10.27 mL, 0.059 mol) The mixture was stirred in isopropanol for 16 hours at room temperature. The reaction mixture was concentrated in vacuo, redissolved in EtOAc, and washed sequentially with 0.5N HCl, a saturated aqueous solution of NaHCO ₃ , and saline. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude oil that was further subjected to chromatography (50% EtOAc / 50% hexanes) to give the desired compound 4.

Process 3
Compound 5 (30 mg, 0.075 mmol, prepared according to WO 2005/095400), Compound 4 (23 mg, 0.075 mmol), Pd (Ph ₃ P) ₄ (9 mg, 0.0078 mmol) and sodium carbonate 2M (115 μL) , 0.23 mmol) in 1 mL DME was sonicated at 150 ° C. for 10 min. The reaction mixture was concentrated to dryness and then filtered through a short pad of silica gel using 30% EtOAc-70% hexane as eluent to give the crude intermediate that was used directly in the next step.

  The crude intermediate was dissolved in 1 mL anhydrous methanol and 200 μL of 25% sodium methoxide / methanol was added. The reaction mixture was stirred at 60 ° C. for 1 h and quenched with 6N HCl (154 μL). The mixture was dried under a nitrogen atmosphere and purified by reverse phase HPLC (10-60 MeCN / water / 0.5% TFA) to give the desired material of formula 6a.

  Compounds of formula 6b and 6c can be prepared in a similar manner using appropriate starting materials. For example, a compound of formula 6b can usually be prepared by replacing compound 1 with tert-butyl 2- (2,2,2-trifluoroethylcarbamoyl) pyrrolidine-1-carbonate, while a compound of formula 6c is usually It can be prepared by replacing compound 1 with tert-butyl 2- (2,2,2-trifluoroethylcarbamoyl) propan-2-ylcarbamate.

Example 2 Analysis Results Tables 4, 5 and 6 below show exemplary ¹ H-NMR data (NMR) and liquid chromatography mass spectral data (mass + proton (M + H)) of specific compounds of the present invention. As measured by electrospray) and residence time (RT). The compound numbers in Tables 4, 5 and 6 correspond to the compounds represented in Tables 1, 2 and 3, respectively (blank indicates that the test was not performed).

Example 3 JAK3 Inhibition Assay Compounds were screened for the ability to inhibit JAK3 using the assay shown below. The reaction was performed in a kinase buffer containing 100 mM HEPES (pH 7.4), 1 mM DTT, 10 mM MgCl ₂ , 25 mM NaCl, and 0.01% BSA. The substrate concentration in the assay was 5 μM ATP (200 uCi / μmol ATP) and 1 μM poly (Glu) ₄ Tyr. The reaction was carried out at 25 ° C. and 1 nM JAK3.

To each well of a 96 well polycarbonate plate, 1.5 μl of candidate JAK3 inhibitor was added along with 50 μl of kinase buffer containing 2 μM poly (Glu) ₄ Tyr and 10 μM ATP. This was then mixed and 50 μl of kinase buffer containing 2 nM JAK3 enzyme was added to initiate the reaction. After 20 minutes of reaction at room temperature (25 ° C.), the reaction was stopped with 50 μl of 20% trichloroacetic acid (TCA) containing 0.4 mM ATP. The entire contents of each well were then transferred to a 96 well glass fiber filter plate using a TomTek Cell Harvester. After washing, 60 μl scintillation fluid was added and ³³ P incorporation was detected with a Perkin Elmer TopCount.

Example 4 JAK2 Inhibition Assay Assay as described above in Example 3 except that the JAK-2 enzyme was used, the final poly (Glu) ₄ Tyr concentration was 15 μM, and the final ATP concentration was 12 μM. Carried out.

  Compounds 22, 35, 56, 68, 177, 223, 310, 317, 318, 319, 320, 321, 322, 326, 336, 337, 338, 339, 340, 351, 356, 367, 369, 370, 388 All compounds represented in Tables 1, 2 and 3 were found to inhibit JAK3 with a Ki of less than 0.1 μM, with the exception of 390 and 390. All compounds in Tables 1, 2 and 3 except for compounds 68 and 319, inhibited JAK3 with a Ki of less than 2.0 μM. Except for compounds 9, 22, 35, 56, 57, 68, 310, 317, 38, 319, 320, 321, 336, 338, 339, 340, 348, 351, 356, 367 and 372, Tables 1, 2 And all 3 compounds were found to inhibit JAK2 with a Ki of less than 0.5 μM. All Tables 1, 2 and 3 compounds, with the exception of compounds 68, 318 and 319, inhibited JAK2 with a Ki of less than 5.0 μM.

<Example 5> JAK3 cell inhibition assay HT-2 clone A5E cells (ATCC Cat. # CRL-1841) were supplemented with cell culture medium (RPMI1640 medium: 2 mM L-glutamine in a humidified 37 ° C incubator. 1.5 g / L sodium bicarbonate, 4.5 g / L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 0.05 mM 2-mercaptoethanol, 10% fetal bovine serum, and ConA And grown and maintained in 10% by volume of rat T-STIM factor [Fisher Scientific Cat # CB40115]. On the test day, HT-2 cells were washed and resuspended in fresh cell culture medium without T-STIM at a concentration of 5 × 10 ⁶ cells / ml and incubated for 4 hours in the absence of T-STIM. After 4 hours, 50 μl (0.25 × 10 ⁶ cells) of the resuspended cell suspension was added to each well of a 96-well plate. Serial dilution series of compounds in DMSO were prepared and then added to RPMI. 100 μl of diluted compound solution was added to each well and the plate was incubated at 37 ° C. for 1 hour. 50 μl of 40 ng / ml (R & D System Cat # 402-ML) of recombinant rat interleukin 2 (rmIL-2) was added and the plate was incubated at 37 ° C. for 15 minutes.

  The plate was centrifuged at 1000 rpm for 5 minutes, the supernatant was aspirated and 50 μl of 3.7% formaldehyde in phosphate buffered saline (PBS) was added to the wells. Plates were incubated for 5 minutes at room temperature on a plate shaker. The plate was centrifuged again at 1000 rpm for 5 minutes. The supernatant was aspirated, 50 μl of 90% methanol was added to each well, and the plate was incubated on ice for 30 minutes. The supernatant was aspirated and the plate was washed with PBS. Phospho STAT-5 (Y694) PE conjugated antibody (PS-5 PE antibody, Becton-Dickinson Cat. # 61256) diluted 1:10 was added to the plate at 25 μl per well and the plate was incubated on a plate shaker at room temperature Incubated for 45 minutes. 100 μl PBS was added and the plate was centrifuged. The supernatant was aspirated and the cells were resuspended in 100 μl PBS. The plate was then measured with a 96-well FACS reader (Guava PCA-96).

  The compounds of the present invention were found to inhibit JAK3 in this assay.

<Example 6> JAK2 cell inhibition assay TF-1 cells (ATCC Cat. # CRL-2003) were supplemented with a cell culture medium (RPMI1640 medium: 2 mM L-glutamine in a 37 ° C. incubator, 1 0.5 g / L sodium bicarbonate, 4.5 g / L glucose, 10 mM HEPES, 1.0 mM sodium pyruvate, 10% fetal bovine serum and recombinant human granulocyte-macrophage colony stimulating factor [rhGMCSF , R & D Systems Cat. # 215-GM]). On the test day, TF-1 cells were washed and resuspended in fresh cell culture medium without rhGMCSF at a concentration of 5 × 10 ⁶ cells / ml and incubated for 4 hours in the absence of rhGMCSF. After 4 hours, 50 μl (0.25 × 10 ⁶ cells) of resuspended cells were added to each well of a 96-well plate. Serial dilutions of compounds were prepared in DMSO and then added to RPMI. 100 μl of diluted compound was added to each well and the plate was incubated at 37 ° C. for 1 hour. 50 μl of 10 ng / ml rhGMCSF was added and the plate was incubated at 37 ° C. for 15 minutes. The plate was subjected to FACS analysis as detailed in Example 5. The compounds of the present invention were found to inhibit JAK2 in this cell assay.

  Although we have described numerous embodiments of the present invention, our basic examples may be modified to provide other embodiments using the compounds and methods of the present invention. It is obvious. Accordingly, it is recognized that the scope of the invention should be defined by the appended claims rather than the specific embodiments presented for purposes of illustration above.

Claims (50)

Compound represented by formula (I):

(I)
Or a pharmaceutically acceptable salt thereof.
(Wherein R ³ is hydrogen, Cl or F, X ¹ is N or CR ⁴ and R ² is hydrogen, F, R ′, OH, OR ′, COR ′, COOH, COOR ′, CONH _2. , CONHR ′, CON (R ′) ₂ or CN, and R ⁴ is hydrogen, F, R ′, OH, OR ′, COR ′, COOH, COOR ′, CONH ₂ , CONHR ′, CON (R ′) ₂ Or CN, or R ² and R ⁴ together form a 5-7 membered aryl or heteroaryl ring optionally substituted with 1 to 4 R ¹⁰ , wherein R ′ is 1 to C _1-3 aliphatic optionally substituted with 4 R ⁵ , each R ⁵ is halogen, CF ₃ , OCH ₃ , OH, SH, NO ₂ , NH ₂ , SCH ₃ , NCH ₃ , CN or unsubstituted C _1-2 or are independently selected from aliphatic, or two R ⁵ groups thereof forming Together with the carbon atom form a cyclopropyl ring or C = O, each ^{R 10} is _{halogen, OCH 3, OH, NO 2} , NH 2, SH, SCH 3, NCH 3, CN or unsubstituted _{C 1-2} aliphatic R ¹ is independently selected from

And R ″ is hydrogen or —C _1-2 aliphatic optionally substituted with 1 to 3 —R ¹¹ , wherein each R ¹¹ is halogen, OCH ₃ , OH, SH, Independently selected from NO ₂ , NH ₂ , SCH ₃ , NCH ₃ , CN, CON (R ¹⁵ ) ₂ or unsubstituted C _1-2 aliphatic, or the two R ¹¹ groups to which they are attached Together with a cyclopropyl ring or C = O, R ⁶ is a C _1-4 aliphatic optionally substituted with 1 to 5 R ¹² , each R ¹² is halogen, OCH ₃ , OH, Independently selected from NO ₂ , NH ₂ , SH, SCH ₃ , NCH ₃ , CN or unsubstituted C _1-2 aliphatic, or two R ¹² groups together with the carbon to which they are attached, the cyclopropyl ring And ring A is up to two selected from N, O or S A 4- to 8-membered saturated nitrogen-containing ring optionally containing 1 to 4 R ¹³ , each R ¹³ being halogen, R ′, NH ₂ , NHR ′, Independently selected from N (R ′) ₂ , SH, SR ′, OH, OR ′, NO ₂ , CN, CF ₃ , COOR ′, COOH, COR′OC (O) R ′, or NHC (O) R ′ Or any two R ¹³ groups are optionally in 1 to 3 R ⁵ groups, with one or more atoms to which each R ¹³ group is attached, in the same or different substituents. C ₁ may optionally be substituted to form a 3-7 membered saturated, unsaturated, or partially saturated carbocyclic or heterocyclic ring, and R ⁸ may be optionally substituted with 1 to 5 R ^12. _-4 aliphatic, or ^{R 9} is _{C 1-2} alkyl, or, ^{R 8} and ^{R 9} are both 1-5 R ² optionally form a carbocyclic or saturated ring heterocyclic 3-7 membered optionally substituted by, R ¹⁴ is hydrogen or unsubstituted C _1-2 alkyl, R ¹⁵ is hydrogen or unsubstituted C _1-2 alkyl, R ⁷ is a C _2-3 aliphatic or alicyclic group optionally substituted with up to 6 F.) The compound of claim 1, wherein the compound has the formula IA.

(IA). The compound according to claim 1, wherein R ³ is hydrogen or chlorine. R ³ is chlorine The compound of claim 3, wherein. R ³ is hydrogen The compound of claim 3, wherein. R ² is hydrogen, fluorine, R is ', OH or OR', the compound of any one of claims 1 to 5. R ² is hydrogen or fluorine, compound of claim 6. 6. The compound of formula IA, wherein R ⁴ is hydrogen, fluorine, R ′, OH or OR ′, or R ² and R ⁴ together form a 6-membered aryl ring. The compound of any one of these. The compound according to claim 8, wherein R ⁴ is hydrogen or fluorine. R ² is hydrogen when R ⁴ is fluorine, R ⁴ is hydrogen when R ² is fluorine, compound of claim 9. R ² and ^{R 4} are both hydrogen, compound of claim 9. R ³ is chlorine, any one compound according to claim 10 or 11. R ³ is hydrogen, any one compound according to claim 10 or 11. R ⁷ is CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ CHF ₂ , CH ₂ CH ₂ F, CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ CF ₃ , CH ₂ CH ₂ CH ₂ F or CH ₂ CH ₂ it is CHF _2, any one compound as claimed in claim 1 13. R ⁷ is _{CH 2 CH 3, CH 2 CF} 3, CH 2 CH 2 CH 3 or _CH 2 _CH 2 CF _3, claim 14 A compound according. R ⁷ is _CH 2 CF _3, claim 15 A compound according. R "is hydrogen or CH _3, any one compound as claimed in claims 1 to 16.   18. A compound according to claim 17, wherein R "is hydrogen. 19. A compound according to any one of claims 1 to 18 wherein ^R14 is hydrogen. 20. A compound according to any one of claims 1 to 19, wherein ^R15 is hydrogen. 2. A compound according to claim 1 wherein the compound is of formula II or III.


(II) or (III)
Wherein X ^1A is N, CH or CF, and R ^1A is

It is. ) R ⁷ is _{CH 2 CH 3, CH 2 CF} 3, CH 2 CH 2 CH 3 or _CH 2 _CH 2 CF _3, claim 21 A compound according. R ⁷ is _CH 2 CF _3, claim 22 A compound according. R ⁶ is

24. A compound according to any one of claims 1 to 23, selected from: R ⁶ is

25. The compound of claim 24, selected from: R ⁶ is

26. The compound of claim 25, selected from: Ring A is

24. The compound according to any one of claims 1 to 23, wherein R < ¹³ >'is hydrogen or R < ¹³ >. Ring A is

28. The compound of claim 27, wherein Ring A is

29. The compound of claim 28, wherein R ¹³ is absent, 29. A compound according. Ring A is substituted with one R ^13, claim 29 A compound according. R ¹³ is _{OH, CH 3, F, OR} ' or NHR', 31. A compound according. 33. The compound of claim 32, wherein R 'is _C1-2 alkyl or _C2-3 alkenyl. R ¹³ is OH, 32. A compound according. R ⁸ and R ⁹ are both

24. A compound according to any one of claims 1 to 23, wherein one or more carbon atoms in the ring are independently optionally substituted with N, O or S. R ⁸ and R ⁹ are

24. The compound according to any one of claims 1 to 23, wherein R ⁸ and R ⁹ are

40. The compound of claim 36, wherein R ⁸ and R ⁹ are

38. The compound of claim 37, wherein 39. A compound according to any one of claims 21 to 38, wherein ^X1A is CH or CF.   A compound selected from Table 1, Table 2 or Table 3.   41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier, adjuvant or excipient.   In addition, chemotherapeutic drugs or antiproliferative agents, anti-inflammatory agents, immunomodulators or immunosuppressants, neurotrophic factors, drugs for treating cardiovascular diseases, drugs for treating destructive bone diseases, liver diseases 42. A therapeutic agent selected from an agent for treating, an antiviral agent, an agent for treating a blood disorder, an agent for treating diabetes, or an agent for treating an immunodeficiency disorder. Composition.   43. A method of inhibiting JAK kinase activity in a biological sample comprising the compound of any one of claims 1 to 40 or the composition of any one of claims 41 or 42 and the biology. A method comprising contacting the target sample.   43. A method of inhibiting a patient's JAK kinase activity comprising administering to the patient a compound according to any one of claims 1 to 40 or a composition according to any one of claims 41 or 42. Including methods.   Treating or seriously treating a disease symptom selected from a proliferative disorder, heart disorder, neurodegenerative disorder, autoimmune disorder, organ transplant disorder, inflammatory disorder, immunodeficiency or immunologically mediated disorder in a patient 41. A method of alleviating dexterity, comprising administering to the patient a compound of any one of claims 1 to 40, or a composition containing the compound.   A chemotherapeutic or antiproliferative agent, anti-inflammatory agent, immunomodulatory or immunosuppressive agent, neurotrophic factor, agent for the treatment of cardiovascular disease, agent for the treatment of diabetes, or immunodeficiency 46. The method of claim 45, further comprising administering an additional therapeutic agent selected from agents for treating the disease, wherein the additional therapeutic agent is appropriate for the disease to be treated.   The disease or disorder is allergy or type I hypersensitivity reaction, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS related dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), multiple Sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion / ischemia, stroke, wharf, transplant rejection, graft-versus-host disease, rheumatoid arthritis, solid malignancy, hematological malignancy, leukemia, lymphoma and bone marrow proliferation 46. The method of claim 45, wherein the method is a sex disorder.   48. The method of claim 47, wherein the disease or disorder is asthma.   48. The method of claim 47, wherein the disease or disorder is transplant rejection.   48. The method of claim 47, wherein the disease or disorder is rheumatoid arthritis.